The objective of the proposed work is to synthesize anti-HIV-l drugs that (i) are highly active, (ii) show minimal toxicity, and (iii) have good biostability. The design of a highly active molecule is based on the preliminary results obtained with forty seven unfused heteropolyaromatic compounds substituted with polar chain groups. Members of this group of compounds show very promising anti-HIV-l activity and low toxicity. The preliminary test data together with nucleic acids binding studies strongly suggest that the anti-HIV activity of this class of molecules is due to recognition of specific structural features of viral RNA such as bulged bases in hairpin loops. The proposed new drugs will exhibit strong, stereospecific binding with the RNA (high activity) and minimal interaction with DNA in chromatin (low toxicity). Molecules which stereospecifically bind to RNA will be composed of (i) a twisted unfused aromatic system able to intercalate or partially intercalate with propeller-twisted base-pairs of RNA and/or bulged bases in RNA hairpin loops, and (ii) a chiral substituent able to interact strongly with both the C2'-OH group in the RNA groove through hydrogen bonding and with a phosphate group of the RNA through electrostatic interaction. The synthetic work has been carefully designed to generate rapidly a large number of compounds with very small structural differences. A series of racemic compounds will be prepared first from readily available derivatives of amino acids. The promising compounds, as determined by HIV-tests, nucleic acids binding studies,.and partition coefficients information (obtained by other research groups), will be synthesized in enantiomeric forms and resubmitted for the screenings. These tests will eliminate nonactive (or less active) stereoisomers and will result in a better understanding of the drug-receptor interaction. Simultaneously, QSAR analyses of the biological and biophysical test data will be conducted by this group. The more promising compounds will be submitted. for screening in vivo. Compounds active in vivo will additionally be labeled with 3H or 14C by this synthetic group to facilitate toxicity, organ distribution, and biostability studies. Additional synthetic modifications will be undertaken (with an understanding of the drug-receptor interaction) to improve desirable properties of the active drug after the feedback from in vivo studies is obtained.